For high efficacy and bioavailability of pharmaceuticals, it may be necessary to reach high serum levels of active substances in a very short time, which requires dosage forms that are released as quickly as possible. However, rapid release is often hampered by the poor water-solubility of active substances.
The kinetics of release and therefore the bioavailability of pharmaceuticals is, apart from the disintegration properties of the pharmaceutical form, dependent primarily on the particle size, the particle size distribution and the crystallinity of the active substance. To speed up the release of poor soluble active substances, they are usually micronized, i.e. the solid active substances are comminuted to particle sizes in the micrometer range. Jet mill procedures are usually used for this.
However, micronization, the micronizates produced thereby and use thereof in dosage forms have disadvantages with respect to undesirable amorphization and from the point of pharmaceutical processability. Thibert and Tawashi: “Micronization of pharmaceutical solids”, MML-Series, 1999, Vol. 1, Chap. 1, p. 328-347. The amorphization is more pronounced, i.e. the crystallinity is lower, the finer the granulometry, and thus the higher the energy input required for milling. Therefore it is in fact very fine-grained micronizates, such as are required for rapid release and pulmonary applications, e.g. with an average grain size of 1-1.5 μm, that have a high amorphous fraction, which for certain active substances can be 5-20% or higher, i.e. the crystallinity is 80-95 wt. % or lower.
The partial amorphization in micronization is associated with chemical and physical destabilization of the active substance. Subsequent agglomerations and recrystallizations can further impair release from the pharmaceutical form. These disadvantages become even more apparent, the finer the granulometry, as is desired for rapid release. Therefore, stability problems can arise in the case of micronizates, both as active substance and in the pharmaceutical form in contact with the excipients. Furthermore, micronizates tend to become highly charged, to form dust and to have poor pourability and flowability, so that processing to the pharmaceutical form is only possible in special, expensive processes, e.g. fluidized-bed wet granulation.
For very rapid release, in the case of poorly soluble active substances, particle sizes are required that cannot be achieved by micronization processes, or can be achieved but only together with severe amorphization. Agglomeration and crust formation that already occur during the grinding operation can make grinding more difficult. Furthermore, micronizates have as a rule a relatively wide grain size distribution. For rapid release kinetics, however, a narrow grain size distribution is desirable, with both the proportions of nanoparticles and the proportions of larger particles being minimized.
Micronizates can be combined with excipients by means of preformulations so that some disadvantageous properties, such as poor processability, are improved. DE 103 25 989 A1 describes active substance—excipient micropellets, which are produced on the basis of micronizates by fluid-bed granulation. This technology is, however, linked inseparably with the aforementioned disadvantages, which arise from the destructive, high-energy grinding process and the attainable granulometry. Moreover, these coarse-grained granules are not suitable for low-dose and ultra-low-dose formulations owing to the required uniformity of content of the active substance.
Very fine crystalline particles can be produced by wet-grinding methods with and without additives, for example surfactants, hydrocolloids or sugar, in ball mills or high-pressure homogenizers, as described for example in U.S. Pat. No. 5,145,684, U.S. Pat. No. 5,091,187, and U.S. Pat. No. 5,858,410. In this case, with an extremely high specific energy input, coarse particles are ground to nano size. However, this process takes a long time, and often requires multiple passes of the suspension through the milling chamber. In addition to the high costs of the apparatuses and possible amorphization, contamination through abrasion and wear of the milling equipment is a further disadvantage.
To avoid these disadvantages, to achieve rapid release, active substances can be spray-dried completely amorphously or can be embedded as a molecular dispersion in hydrophilic, polymeric excipients. E. Nürnberg in “Darstellung and Eigenschaften pharmazeutisch relevanter Sprühtrocknungsprodukte”, Acta Pharm. Techn., 26(1), p. 40-67, 1980. This is described in European Patent Application 04103837 A1 with concrete active substances and with reference to specific pharmaceutical applications. These forms have the disadvantage, however, that the good solubility properties are obtained at the expense of considerable risks in chemical stability and with correspondingly high loading also in physical stability.
A special case of molecular embedding for speeding up release is the formation of inclusion complexes with cyclodextrins. However, this method is associated with molecular geometry suitable for complexing and therefore is not of universal application.
Other technology comprises spraying an organic solution of active substance on a carrier, as described for example in DE 19652196 A1. This can take place during fluid-bed granulation for the production of tablet granules or alternatively by spray-drying as a heavily loaded preformulation. The disadvantages of this technology comprise the frequent complete or partial amorphization in the spray-drying of solutions of active substances or else in the production of an unstable crystalline modification. Even with the heavily loaded preformulations described, rapid release is not automatically achieved, as the layers of active substance on the micronized carrier do not dissolve more quickly than comparable active substance micronizates. This technology has its strengths rather in the achievement of good uniformity of content for low-dose or ultra-low-dose formulations and better processing of poorly micronizable active substances. Moreover, the use of flammable solvents increases the technological costs in the production process.
An alternative to micronization and to the use of amorphous or crystalline spray-formulated combinations of active substances and excipients is the production of crystals with a grain size distribution that is adapted to the required release behaviour, by crystallization in a device for wet grinding followed by temperature oscillation, as described in EP 1497308 B1. The particles obtainable by this method are indeed crystalline, but as a rule do not reach the particle size that is necessary for very rapid release. Thus, as a rule not even the average grain size of micronizates is achieved. Furthermore, in fact during crystallization of extremely fine particles from highly supersaturated solutions, the fine primary particle granulometry is lost again through concomitant agglomeration. For forms with very rapid release, this technology has therefore reached its limits.
DE 10214031 A1 describes a precipitation method for the production of micro- and nanoparticles for fast dissolving as well as pulmonary dosage forms. The active substance is dissolved in a solvent and then precipitated with a non-solvent in the presence of a crystal growth inhibitor. The disadvantage of this method is that once again, because of the rapid phase transfer, analogous to spray-drying, amorphous or metastable phases are usually produced. This applies mainly to poorly crystallizable active substances with high configurative entropy, where the stable crystal form is kinetically disadvantaged. The presence of the crystal growth inhibitor means that a phase transfer to the stable modification during the production process is more difficult or is even prevented. This is associated with imponderable stability problems in the pharmaceutical form. Another disadvantage is that despite inhibition of growth, the precipitable grain size is strongly dependent on the physicochemical properties of the active substance and is not always sufficiently fine for very rapid release.
Other methods of production of suspensions of fine-grained particles of active substance by precipitation are described in U.S. Pat. No. 5,389,382, US Patent Application 2005/0139144 and US Patent Application 2002/0127278. Here, however, crystal growth is limited by the precipitation conditions (e.g. mixture ratio), the presence of stabilizers, or by corresponding energetic post-treatment in a high-pressure homogenizer.
Another precipitation method for the production of nanoparticles of active substances is described in DE 10 2005 053 862 A1. Here, just before or in a high-energy zone of small volume (ultrasound cell, shearing clearance of a high-pressure homogenizer, rotor-stator clearance in a colloid mill), the dissolved active substance is mixed with a non-solvent and is precipitated. These high-energy wet-grinding devices modified as precipitation reactors operate continuously by the through-flow principle. In contrast to the pure grinding process, this combination can produce particle sizes well into the nano range. However, this method also has the disadvantage that the equipment is very expensive, and contamination problems (e.g. with sonotrode material) often arise. These arrangements are not suitable for active substances that crystallize slowly or with difficulty, or for those that pass through unstable, e.g. amorphous intermediate phases. Therefore this method is only suitable for organic compounds that crystallize sufficiently rapid.
Another method for producing micro- and nanoparticles is the precipitation using supercritical carbon dioxide. Kerc, et al.: “Micronization of drugs using supercritical carbon dioxide”, Int. J. Pharm. 182, 1999, 33-39; Steckel, et al.: “Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide”, Int. J. Pharm. 152, 1997, 99-110. However, these methods are very expensive in terms of apparatus and technology, because they involve working with supercritical gases.
A fundamental disadvantage of the aforementioned spray-drying and precipitation methods is due to their nature. The majority of active substances are of a polymorphic character, i.e. they are able to crystallize in more than one crystal modification. For pharmaceutical uses, however, with few exceptions, the thermodynamically most stable crystal modification is preferred. According to Ostwald's Rule of Stages, the higher-energy, and thus less stable modifications, amorphous-crystalline mixed forms or even the purely amorphous form, e.g. regularly in the case of spray-drying of solutions, form preferentially from solutions, especially in the case of rapid process kinetics. Phase transformations to the stable modification are difficult to control, even if they occur at all within a reasonable period of time. Because of the high levels of supersaturation, precipitation methods are naturally extremely rapid phase transition processes, and this can lead to problems in the reproducible production of a thermodynamically stable crystal form, especially as this transformation, which can overlap with the precipitation process or may also take place later, can have a considerable adverse effect on the grain size achieved.